Neurogenesis was traditionally believed to occur only during embryonic development in mammals. Only recently has it become generally accepted that new neurons are indeed continuously produced and integrated in discrete regions of the adult mammalian central nervous system. Adult neurogenesis recapitulates the complete process of the neuronal development, from fate specification of neural progenitors, migration, synaptic integration and maturation of newborn dentate granule cells (DGCs). The molecular mechanisms that regulate these neurogenesis steps are largely unknown. Gamma-amino butyric acid (GABA), one of the major inhibitory neurotransmitters in the adult central nervous system, activates GABA receptors in the tonic/phasic mechanisms. Emerging evidence suggests that GABA receptor activity also plays an essential role in regulating the adult neurogenesis. The specific contribution of tonic and/or phasic GABA activation to the proliferation and differentiation of adult neural progenitors and the synaptic integration of their progeny, however, is unknown, and will be examined in our current proposal. Specific Aim I: To determine the roles of tonic GABA receptor activation in regulating proliferation and fate specification of neural progenitors in the adult brain. Specific Aim II: To examine the specific roles of tonic and/or phasic GABA receptor activation in synapse formation and maturation of newborn DGCs in the adult brain. Specific Aim III: To determine the roles of GABA receptor activation in the formation of functional synapses by the axons of newborn DGCs in the adult brain. The approach will be to use engineered retroviruses to genetically manipulate GABAergic activity of the adult neural progenitors and their progeny. The proliferation and differentiation of these genetically-manipulated adult neural progenitors and the synaptic integration of these newborn neurons will be examined. Understanding these regulatory mechanisms for adult neurogenesis may provide clues into the etiology and pathology of these brain disorders and diseases. More importantly, these studies may shed light on novel therapy development such as functional replacement of damaged neurons in degenerative neurological disease utilizing stem cells, including both embryonic stem cells and adult neural stem cells. PUBLIC HEALTH RELEVANCE: The adult brain is capable of generating new neurons throughout adulthood. These newborn neurons in the adult brain can successfully integrate into the adult brain. However, we have yet to understand how these new neurons are generated and how these neurons can make the right connections with the existing neurons in the brain. The development of these new neurons shares similar mechanisms with embryonic neuronal development, in which the neurotransmitter, gamma-amino butyric acid (GABA) plays an important role. We propose to decipher the mechanisms of GABA receptor activation in regulating adult neurogenesis. Understanding the kind of factors regulating the generation of these new neurons may provide clues into the etiology and pathology of the brain disorders and diseases. Our studies may potentially lead to the development of novel therapy such as functional replacement of damaged neurons in degenerative neurological disease utilizing stem cells, including both embryonic stem cells and adult neural stem cells.